Long term potentiation (LTP)[unreadable] of synaptic transmission is a form of synaptic plasticity that is observed in[unreadable] all principal neurons in the hippocampus-a brain structure implicated in[unreadable] certain forms of long-term memory. LTP has been extensively studied at Schaffer[unreadable] collateral and perforant path synapses, while, for technical reasons,[unreadable] relatively less attention has been paid to mossy fiber synapses in the[unreadable] hippocampus. The mossy fiber synapse has a number of unusual features,[unreadable] including LTP that does not depend on the NMDA type of glutamate receptor, and[unreadable] the mechanisms for the induction and expression of LTP at this synapse are not[unreadable] well understood. In this renewal application we propose to utilize visual[unreadable] patch-clamp techniques, pre- and postsynaptic Ca2+ imaging, focal stimulation[unreadable] of mossy fibers, and whole-cell recordings from single, mossy fiber boutons,[unreadable] all in acute slices of rat hippocampus, to investigate a number of hypotheses[unreadable] derived from our previous studies of this synapse. The aims of this proposal[unreadable] are: 1) To test the hypothesis that Ca2+ is released from stores inside mossy[unreadable] fiber boutons during stimulus protocols that induce LTP; 2) To test the[unreadable] hypothesis that Ca2+ released from intracellular stores postsynaptically during[unreadable] certain stimulus protocols is required for LTP induction; 3) To test the[unreadable] hypothesis that activation of protein kinases A, C, CaMKII, and MAPK is[unreadable] required for LTP induction or expression; 4) To test the hypothesis that[unreadable] brief-train LTP is associative and requires concomitant activity of other[unreadable] pathways for induction, while long-train LTP does not require co-activity of[unreadable] other afferents; and 5) To test hypotheses for a role of mossy fiber activity[unreadable] in the induction of LTP at commissural/associational and perforant path[unreadable] synapses onto CA3 neurons. The so-called "detonator synapse" hypothesis will be[unreadable] tested as part of this aim. We will also test for associative and/or[unreadable] heterosynaptic plasticity between the other synaptic inputs to CA3 neurons and[unreadable] the mossy fibers. We believe that the results of these studies will add[unreadable] significantly to our understanding of the computational properties of the[unreadable] hippocampus and the role of the hippocampus in learning and memory and diseases[unreadable] of cognition.